Midostaurin + Chemo Ups AML Survival

Abstract

In a phase III clinical trial, previously untreated patients with acute myeloid leukemia and FLT3 mutations received either the FLT3 inhibitor midostaurin or a placebo during chemotherapy. Patients who received midostaurin had a 5-year survival rate of 50.9% compared with 43.9% for the placebo group, as well as remissions that lasted nearly a year longer.

For some adults newly diagnosed with acute myeloid leukemia (AML), treatment with the FLT3 inhibitor midostaurin (PKC412; Novartis) in combination with chemotherapy may prolong survival, according to a phase III trial. Researchers reported their findings at the American Society of Hematology (ASH) 57th Annual Meeting in Orlando, FL, held in December.

Because AML is so aggressive, only about 40% of patients ages 25 to 64 survive 5 years or longer, according to Cancer Research UK; survival is much shorter for patients age 65 and older. For the roughly 25% of patients with FLT3 internal tandem duplication mutations, the prognosis is particularly poor due to a higher rate of relapse.

The CALGB 10603/RATIFY trial enrolled 717 patients, ages 18 to 60, newly diagnosed with AML and positive for various FLT3 mutations. They were randomly assigned to receive midostaurin or a placebo. In addition, both groups received standard chemotherapy and, if the treating physician felt it appropriate, a stem cell transplant. Patients who achieved remission continued to receive midostaurin or placebo as maintenance therapy for up to 1 year.

The 5-year survival rate for patients receiving midostaurin was 50.9% compared with 43.9% for the placebo group. There was no difference in the remission rate or the number of patients who received stem cell transplants, but midostaurin did increase the median length of remission from 14.4 to 25.9 months, said Richard Stone, MD, director of the adult acute leukemia program at Dana-Farber Cancer Institute in Boston, MA, who presented the findings.

Oncologist Neil Shah, MD, PhD, program leader of the hematopoietic malignancies program for the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, was surprised by the results. “Midostaurin is not the most potent FLT3 inhibitor we have tested in the clinic, as evidenced by the minimal activity it exhibited as monotherapy” in a phase IIb trial in which midostaurin alone was given to patients whose cancers had returned or who were ineligible for chemotherapy: Only one patient experienced a partial remission.

Newer FLT3 inhibitors, such as ASP2215 (gilteritinib; Astellas Pharma) and AC220 (quizartinib; Daiichi-Sankyo), which more selectively target FLT3, decrease the number of blood and bone marrow blasts more than midostaurin, which acts on several tyrosine kinases. In a phase II trial of ASP2215 in patients with relapsed or refractory AML, also reported at the ASH meeting, 55% of participants had a complete or partial remission. Given the effectiveness of the midostaurin–chemotherapy combination, Shah is optimistic that ASP2215, AC220, and another FLT3 inhibitor, PLX3397, might also prove beneficial.

“It's an open scientific question about whether a more specific drug in this context would have been better, or whether the fact that midostaurin is a multitargeted [kinase inhibitor] made it better,” says Stone. He hopes to initiate another trial to compare the effect of combining a more selective FLT3 inhibitor, such as ASP2215, with midostaurin and chemotherapy in untreated patients with AML.

One limitation of the study, Shah noted, is that mutations in other genes, such as DMNT3A and NPM1, which have been linked to poor therapeutic responses, weren't considered. This may have created an imbalance between the treatment and control groups. Stone says that he and his colleagues plan to further assess the patient responses, taking these mutations into account. –Kim Smuga-Otto